CD40 Deficiency

CD40 deficiency is an autosomal recessive combined immunodeficiency from biallelic loss-of-function variants in CD40 (TNFRSF5). It produces the same hyper IgM picture as CD40 ligand deficiency, but both sexes are affected.

Pathophysiology. CD40 on B cells, macrophages, dendritic cells and epithelium does not receive its signal from CD40 ligand. B cells cannot switch class from IgM, germinal centres fail, and macrophage activation against intracellular organisms is weak.

It is very rare and is mostly reported in consanguineous families. Onset is in infancy or early childhood.

Pneumocystis infection, Cryptosporidium cholangiopathy and neutropenia dominate.

• Pneumocystis pneumonia in infancy
• Recurrent sinopulmonary infection
• Neutropenia with mouth ulcers
• Chronic diarrhoea, Cryptosporidium infection and sclerosing cholangitis
• Opportunistic infection: Cryptosporidium, CMV, Cryptococcus
• Autoimmune cytopenias
• Lymphadenopathy is absent or small, since germinal centres are lacking

• Immunoglobulins: low IgG and IgA, with normal or high IgM.
• CD40 expression on B cells by flow cytometry (absent or reduced), with normal CD40 ligand expression on activated T cells, and sequencing of CD40 (biallelic variants) with parental testing.
• Full blood count with differential, repeated.
• Lymphocyte subsets: normal B cells, IgM and IgD positive, with no class switched memory cells.
• Pneumocystis PCR, stool Cryptosporidium PCR, viral PCR.
• Liver enzymes, ultrasound and cholangiography.

Differential diagnosis.

• CD40 ligand deficiency (X-linked)
• Activation induced cytidine deaminase and UNG deficiency
• ICOS deficiency and common variable immunodeficiency
• Severe combined immunodeficiency
• NEMO deficiency
• Secondary neutropenia

• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Pneumocystis prophylaxis from diagnosis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Pneumocystis pneumonia: co-trimoxazole with trimethoprim 15 to 20 mg/kg daily in 3 to 4 divided doses, intravenously or orally, for 21 days (halve at creatinine clearance 15 to 30 mL/min). Add prednisolone for hypoxaemia (PaO2 under 9.3 kPa): 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days (children 1 mg/kg twice daily, then tapered over the same schedule).
• Neutropenia: filgrastim 1 to 5 microgram/kg subcutaneously daily or on alternate days, titrated to keep neutrophils at 1.0 x 109/L or more.
• Cryptosporidium prevention and treatment: boiled or filtered water, and nitazoxanide 500 mg orally twice daily for 3 to 14 days (aged 12 years and over; younger children by weight under specialist direction).
• Liver disease: ursodeoxycholic acid 15 mg/kg orally daily in divided doses, with ultrasound and liver enzymes every 6 months.
• Haematopoietic stem cell transplantation is the definitive treatment, ideally before chronic lung or liver damage.
• Vaccines: inactivated only; avoid live vaccines.

Special groups.

• Families with a known variant: genetic counselling, since each pregnancy has a 1 in 4 risk, and prenatal or early postnatal testing.

Monitoring. Trough IgG every 3 months. Full blood count with differential monthly while neutropenic. Liver enzymes and ultrasound every 6 months. Lung imaging or function yearly.

Referral and escalation. Refer urgently to immunology and a transplant centre. Emergency for respiratory distress, fever with neutropenia, or jaundice.